Friday, January 11, 2008

Toxicity, Methamphetamine PART 1

Toxicity, Methamphetamine
Last Updated: July 12, 2006
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Synonyms and related keywords: amphetamine, ice, crystal, meth, crystal meth, methamphetamine use, stimulant, euphoria, methamphetamine-intoxication, speedballing, myocardial infarction, palpitations, agitation, anxiety, hallucinations, amphetamine-induced seizures, emotional lability, confusion, paranoia, suicidal ideation, delusions, despondent affect, drug-induced psychosis, acute toxic psychosis, methamphetamine-induced seizures, hyperthermia, coma, muscle hyperactivity, metabolic acidosis, secondary rhabdomyolysis, renal failure, shock, lichenoid drug eruption, tachycardia, hypertension, atrial arrhythmias, ventricular arrhythmias, myocardial ischemia, atherosclerosis, severe orthostatic hypotension, acute cardiomyopathy, chronic cardiomyopathy, cardiac toxicity, amphetamine-induced hypertension, necrotizing angiitis, arterial aneurysms, arterial sacculations, acute aortic dissections, bacterial endocarditis, fungal endocarditis, abnormal cardiac valves, secondary dilated cardiomyopathy, septic embolism, mycotic aneurysm, seizures, psychosis, choreoathetoid movement disorders, cerebrovascular accidents, cerebral edema, cerebral vasculitis, coma, clonus, respiratory failure, spontaneous cerebral hemorrhaging, amphetamine-induced cerebral vasculitis, cerebral artery spasm, cerebral artery occlusion, ischemic strokes, transient cortical blindness, pneumomediastinum, pneumothorax, pneumopericardium, acute noncardiogenic pulmonary edema, pulmonary hypertension, hypoxemia, rhabdomyolysis, cardiovascular shock, acute tubular necrosis, renal necrotizing angiitis, amphetamine-induced acute interstitial nephritis, hepatocellular damage, giant GI ulcers, ischemic colitis, smoking methamphetamine HCl powder

Author: Robert Derlet, MD, Professor of Emergency Medicine, University of California at Davis School of Medicine; Chief, Division of Emergency Medicine, UC Davis Health System
Coauthor(s): Timothy Albertson, MD, PhD, Vice-Chair of Clinical Affairs, Chief, Professor of Anesthesiology, Medical Pharmacology and Toxicology, Departments of Internal Medicine and Anesthesiology, University of California at Davis Medical Center
Robert Derlet, MD, is a member of the following medical societies: American Academy of Emergency Medicine, American Association for the Advancement of Science, Infectious Diseases Society of America, Society for Academic Emergency Medicine, and Wilderness Medical Society
Editor(s): Edward A Michelson, MD, Program Director, Associate Professor, Department of Emergency Medicine, University Hospital Health Systems in Cleveland; John T VanDeVoort, PharmD, Clinical Assistant Professor, College of Pharmacy, University of Minnesota; Fred Harchelroad, MD, FACMT, Chair, Department of Emergency Medicine, Director of Medical Toxicology, Associate Professor, Department of Emergency Medicine, Allegheny General Hospital; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Asim Tarabar, MD, Assistant Clinical Professor of Emergency Medicine, Yale University School of Medicine; Consulting Staff, Department of Emergency Medicine, Yale-New Haven Hospital
Background: Methamphetamine use has increased rapidly in the United States and now involves all regions of the country.
Methamphetamine and related compounds can produce euphoria and stimulant effects. In addition, it may generate many of the same toxic effects seen with other stimulants such as cocaine. The ease of synthesis from inexpensive and readily obtainable chemicals has led to the widespread and rampant increase in abuse of this dangerous drug. Many US emergency departments (EDs) now treat as many methamphetamine-intoxicated patients as cocaine-intoxicated patients.
The euphoria produced by methamphetamine appears similar to that produced by cocaine. Methamphetamine may be taken orally, intravenously, or in a smokable form. Patients who inhale the smokable form of methamphetamine (ie, ice) experience an immediate euphoria similar to that of crack cocaine, but the effects may last much longer.
Individuals who abuse methamphetamine range widely in age, socioeconomic status, and ethnic background. Recently, epidemic abuse has been described in some groups of adolescents; they cite availability, low cost, and a longer duration of action than cocaine as reasons for their drug preference.
The medical history of amphetaminelike compounds extends back nearly 100 years. A Japanese pharmacologist first synthesized methamphetamine in 1919. A more detailed analysis of the pharmacology of amphetamine derived from the basic phenylethylamine structure was reported in 1930. Amphetamine was introduced in the 1930s in the form of inhalers for treating rhinitis and asthma. The stimulant, euphoric, and anorectic effects of amphetamine were recognized quickly, leading to its abuse. In 1937, a report stating that amphetamine could enhance intellectual performance through enhanced wakefulness further contributed to the popularity and early abuse of amphetamine. Amphetamines were used extensively by Allied and Axis armed forces during World War II and during the 1991 Operation Desert Storm, allegedly to increase wakefulness and attention. Recreational abuse of amphetamine has been used to achieve a euphoric state.
Initial federal controls were enacted in the late 1950s, but amphetamine continued to be abused by students, athletes, shift workers, truck drivers, and others into the next decade. The Controlled Substance Act of 1970 stringently regulated the manufacture of amphetamine. Despite the decline of industrially synthesized amphetamines, illicit methamphetamine use continues to increase.
Pathophysiology: Amphetamines stimulate the central nervous system (CNS), which results in one or more clinical effects: inducing euphoria; intensifying emotions; altering self-esteem; and increasing alertness, aggression, and sexual appetite.
In the brain, presynaptic reuptake of catecholamines (ie, dopamine, norepinephrine) is blocked, causing hyperstimulation at selected postsynaptic neuron receptors. Indirect sympathomimetic effects of amphetamines are also caused by blocking presynaptic vesicular storage and by reducing cytoplastic destruction of catecholamines by inhibiting mitochondrial monoamine oxidase. Indirectly, these hyperstimulated neurons can stimulate various other noncatecholaminergic central and peripheral nervous pathways. Sympathomimetic stimulation of central and peripheral pathways by most amphetamines may occur directly but to a much lesser extent than with ephedrine.
Changes in mood, excitation, motor movements, sensory perception, and appetite appear to be mediated more directly by central dopaminergic alterations. It has been postulated that serotonin alterations contribute to the amphetamine-related mood changes, psychotic behavior, and aggressiveness.
In humans, the half-life of methamphetamine ranges from 10-20 hours, depending on the urine pH (half-life is shorter in acidic urine), history of recent use, and dosage. Methamphetamine has greater CNS effects compared to D-amphetamine, presumably because of the prolonged half-life and increased CNS penetration. A significant portion of methamphetamine is metabolized to amphetamine.
Methamphetamine is absorbed readily from the gut, airway, nasopharynx, muscle, placenta, and vagina. Peak plasma levels are observed approximately 30 minutes after IV or IM routes and 2-3 hours postingestion. Rapid tissue redistribution occurs with steady-state cerebrospinal fluid levels of about 80% of plasma levels. Hepatic conjugation pathways with glucuronide and glycine additions can result in inactivation and urine excretion of amphetamine metabolites.
When methamphetamine is used with ethanol, increased psychological and cardiac effects are observed. This is presumed to be the result of pharmacodynamic rather than pharmacokinetic interactions. Similarly, the increased toxicity of simultaneously used opioids and amphetamines, such as methamphetamine (ie, speedballing), appear to result from pharmacodynamic interactions.
The euphoric effects produced by methamphetamine, cocaine, and various designer amphetamines are similar and may be difficult to clinically differentiate. A distinguishing clinical feature is the longer pharmacokinetic and pharmacodynamic half-life of methamphetamine, which may be as much as 10 times longer than the half-life of cocaine.
Animal studies with D-amphetamine and cocaine suggest that some differences in underlying mechanisms of toxicity may exist between these agents. Because of the variability in quality and concentration of illicitly purchased methamphetamines, the clinical observation of toxic effects usually is more relevant than an estimate of total ingested dose. Although hair and saliva analysis have been reported, most toxicological monitoring or testing is performed with urine and blood samples.
Frequency:
In the US: Widespread
Race: No scientific data have found that outcomes of methamphetamine exposure are dependent on race.
Sex: No scientific data have found that outcomes of methamphetamine exposure are dependent on sex.

History: Clinical toxicity of amphetamines and related compounds primarily affect the cardiovascular and central nervous systems. Patients may present with pulmonary symptoms if the drugs are inhaled or smoked.
Cardiovascular signs include the following:
Chest pain, ischemia, or myocardial infarction
Tachycardia and/or palpitations
Central nervous system signs include the following:
Agitation, anxiety, and hallucinations are typical complaints.
Some patients who have used methamphetamine present unconscious to the ED. In these persons, lack of responsiveness may be partially caused by use of other drugs (ie, opioids).
Other patients may be unresponsive because of the direct effects of intravenous methamphetamine use or secondary to amphetamine-induced seizures.
The initial feeling of physical and mental enhancement following amphetamine use can quickly deteriorate with high doses or chronic use, resulting in emotional lability, confusion, paranoia, and hallucinations.
Altered mental status was found in 57% of a series of 127 amphetamine-toxic patients who presented to an ED with agitation, suicidal ideation, hallucinations, delusions, confusion, and despondent affect. These are the most common major signs and symptoms of amphetamine abuse. Patients challenged with large doses of intravenous methamphetamine developed drug-induced psychosis if they were dependent on amphetamine but not if they were naive.
Methamphetamine can induce an acute toxic psychosis in previously healthy persons and precipitate a psychotic episode in those with psychiatric illness.
Methamphetamine-induced seizures have been viewed as isolated events or associated with hyperthermia, coma, muscle hyperactivity, metabolic acidosis, secondary rhabdomyolysis, renal failure, and shock.
Respiratory signs include the following:
Dyspnea
Wheezing
Increases and decreases in sexual desire and activity have been reported with amphetamine use.
Methamphetamine use and/or abuse during pregnancy can be fatal to the mother and result in spontaneous abortion or teratogenesis to the fetus. Methamphetamine has been shown to cause placental vasoconstriction and interfere with placental monoamine transporters.
Although not formally studied, the most common dermatological manifestations in patients who abuse amphetamine-related compounds are probably related to self-induced skin picking, intravenous needles, or burns.
A case of lichenoid drug eruption has been reported with the use of methamphetamine.
Physical:
Cardiovascular
Tachycardia and hypertension may be observed.
Atrial and ventricular arrhythmias and myocardial ischemia have been noted.
Chest pain, associated with cardiac ischemia, following methamphetamine use may occur. Patients are at risk for cardiac ischemia because of accelerated atherosclerosis from chronic drug use and other less well-understood mechanisms. Concern that thrombus formation may be contributing to amphetamine-related myocardial infarction has generated at least one case report on the use of thrombolytics, in addition to the use of nitrates and analgesics, in patients with chronic drug use.
Significant hypotension with bradycardia and metabolic acidosis has been observed in massive amphetamine overdoses.
Suppression of vasomotor outflow leading to severe orthostatic hypotension because of amphetamine intoxication also has been reported. This suggests that multiple mechanisms contribute to the development of circulatory collapse with amphetamine abuse.
Acute and chronic cardiomyopathy is thought to be secondary to direct amphetamine cardiac toxicity and indirectly from amphetamine-induced hypertension, necrosis, and ischemia. Although most reports of cardiomyopathy have implicated oral and intravenous amphetamines as causes, smoking of methamphetamine has also been documented as a cause.
Necrotizing angiitis with arterial aneurysms and sacculations have been observed in the kidney, liver, pancreas, and small bowel of methamphetamine drug abusers.
Similarly, acute aortic dissections and arterial aneurysms have been associated with methamphetamine abuse.
With the illicit use of any intravenous drug, bacterial or fungal endocarditis can lead to abnormal cardiac valves, secondary dilated cardiomyopathy, septic embolism, and mycotic aneurysm. Recently, some individuals orally taking fenfluramine and phentermine for appetite suppression have been found to have valvular abnormalities leading to mitral and aortic regurgitation.
Central nervous system
Seizures and psychosis may occur.
Acute and chronic amphetamine exposures have also been associated with choreoathetoid movement disorders independent of Huntington disease.
Other CNS disorders induced by amphetamines include cerebrovascular accidents caused by hemorrhage or vasospasm, cerebral edema, and cerebral vasculitis. Coma, clonus, and respiratory failure are characterized in a recent report of massive dexfenfluramine overdose.
Spontaneous cerebral hemorrhaging has been reported in patients using amphetamines, as well as in patients with preexisting arteriovenous malformations and with amphetamine-induced cerebral vasculitis.
Cerebral artery spasm and occlusion, leading to ischemic strokes and transient cortical blindness, have been noted following methamphetamine use.
Respiratory
Barotrauma, including pneumomediastinum, pneumothorax, and pneumopericardium
Acute noncardiogenic pulmonary edema
Pulmonary hypertension
Renal and hepatic
Renal failure associated with amphetamines has been related to hypoxemia, rhabdomyolysis, necrotizing angiitis, and cardiovascular shock with subsequent acute tubular necrosis.
Renal necrotizing angiitis, noted in some cases of renal failure, has been observed in the presence of hepatitis B serum antigen and is usually found in those who use intravenous amphetamines.
In one case report, amphetamine-induced acute interstitial nephritis was thought to be the cause of renal failure.
Hepatocellular damage has been reported with amphetamine, malondialdehyde (MDA), and 3,4-methylelenedioxy-methamphetamine (MDMA) after acute and chronic abuse. Direct toxic effects (eg, hypotension, hepatotoxic, contaminants, hepatic vasoconstriction, lipid peroxidation, occult viral causes, necrotizing angiitis) have been postulated as mechanisms for amphetamine-induced hepatocellular toxicity.
Abuse of methamphetamine has also been associated with the formation of giant GI ulcers and ischemic colitis.
Causes:
Illicit production of methamphetamine
Methamphetamine is relatively easy to synthesize, and illicit production occurs in home kitchens, workshops, recreational vehicles, and rural cabins.
Methamphetamine is a derivative of phenylethylamine. The substances differ structurally in that a methyl group attaches to the terminal nitrogen to form methamphetamine.
The federal government and some states have enacted laws decreasing the availability of necessary precursor chemicals. Many of these agents can still be obtained in neighboring states or countries.
Synthesis
A common method of synthesis begins with L-ephedrine, which is reduced to methamphetamine using hydriodic acid and red phosphorus.
Alternative approaches include using a different acid, a different catalyst, or a substituted ephedrine (eg, chloroephedrine, methylephedrine).
The methamphetamine produced by ephedrine reduction is a lipid-soluble pure base form, which is fairly volatile and can evaporate if left exposed to room air temperature. This product is converted to the water-soluble form, methamphetamine hydrochloride (HCl) salt.
Illicitly synthesized methamphetamine may be contaminated by nonstimulant organic or inorganic impurities. Poisoning from heavy metals, such as lead and mercury, or from solvents used in the synthesis process have been reported. Exposures to carcinogenic materials have been noted.
Street methamphetamine may be mixed with many drugs, including cocaine. Studies show that 8-20% of street-available stimulants contain both drugs. In a report on cocaine intoxication, 7% of patients sought medical help because of concurrent use of cocaine and amphetamines.
Fatalities related to amphetamine use have been associated with assaults, suicides, homicides, accidents, driving impairment, and maternal-fetal and infant exposures
In 1987, approximately one eighth of all homicides in San Diego County involved methamphetamine.
In a recent study of drug abuse and alcohol consumption related to motor vehicle accidents in Belgium, amphetamine was the most commonly found drug other than alcohol. A study of 28 drivers arrested or killed in traffic accidents with blood samples positive for methamphetamine showed that typical driving behaviors include aggressive and erratic driving with high-speed collisions.
Making ice, the smokable form of methamphetamine, from standard quality methamphetamine HCl is essentially a purification process. Methamphetamine HCl is added slowly to water that has been heated 80-100°C until a supersaturated solution is obtained. When the slurry is cooled, pure HCl salt of methamphetamine (ice) precipitates. Methamphetamine HCl, unlike cocaine HCl, is volatile and can be smoked. Other solvents, such as isopropanol, have been used in place of water to speed the process. Uncontrolled variations of this process can result in unreliable removal or addition of impurities. The physical characteristics of the final product depend on the quality and type of reagents used and on contaminants that may have been introduced. The lack of significant further processing of methamphetamine HCl has resulted in increased availability and popularity of smoking the drug.
One reason for the popularity of smoked methamphetamine is the immediate clinical euphoria that results from the rapid absorption in the lungs and deposition in the brain.
Smoking methamphetamine HCl powder, crystals, or ice occurs first by placing the substance into a piece of aluminum foil that has been molded into the shape of a bowl, a glass pipe, or a modified light bulb and heating it over the flame of a cigarette lighter or torch. Then, the volatile methamphetamine fumes are inhaled through a straw or pipe.